Abstract: There is currently no clinically approved biomedical prevention strategy to prevent sexual HIV-1 transmission, which is the leading cause of new HIV infections worldwide. Although suboptimal alone, microbicide and vaccine strategies implemented together could fundamentally alter HIV prevention by providing protection during the immunization period, reducing infectious challenge, or boosting virus-specific mucosal immunity. Vaccine strategies that recruit and activate antigen-presenting cells, particularly DCs, at the site of immunization while at the same time inhibiting their capacity to enhance HIV-1 transmission may tip the balance towards boosting immunity rather than promoting infection. We have developed a nanoparticle microbicide and mucosal vaccine combination to generate a niche in the vaginal mucosa where mucosal DCs are recruited for immune activation but are protected from HIV-1 infection. We hypothesize that immunizing microbicide nanoparticles will recruit and activate DCs at the site of vaccination where HIV-1 infection and transmission are rendered non-permissive. In this New Innovator Award, I plan to engineer DC chemo- attracting nanocarriers that elute ARV drugs, demonstrate that enhanced DC uptake and processing of immunogens delivered from these nanocarries correlates with increased immunological responses, and test the nanocarriers in a relevant animal model to measure the quality and magnitude of the antigen-specific mucosal antibody and cellular immune responses that are elicited. This research proposal is particularly well suited for this unique funding mechanism because it proposes innovative, high-risk, and high-reward research at the interface of bioengineering and immunology that would have a major impact on HIV/AIDS research and prevention. The proposal is highly innovative because it integrates nanotechnology with HIV-1 pathogenesis and prevention immunology to design novel strategies based on newly emerging but unexplored concepts in chemo-vaccination to protect mucosal tissue from pathogen invasion. The approach is risky because evidence suggests that the lower female genital tract is a poor inductive site for adaptive immunity. The successful outcome of this research has the potential to fundamentally alter how microbicides and vaccines are used for HIV prevention, create a mechanism for effective immunization in the lower female genital tract, and provide a strategy for vaccination at other mucosal tissue. Public Health Relevance: Developing a safe and effective preventive HIV vaccine is a global health priority. This research proposal integrates knowledge about the chronology and molecular basis of sexual HIV transmission and infection with strategies for biomaterials engineering to deliver chemo-vaccines that will confer protective mucosal immunity.